Chiral phosphorus compound

ABSTRACT

The present invention relates to novel chiral phosphorus compounds which can be readily prepared from quinoline derivatives as inexpensive starting compounds and have the general formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5  are chiral or achiral organic residues which are derived from substituted or unsubstituted straight or branched chain or cyclic aliphatic or aromatic groups and which, in the case of the pairs R 1 /R 2  and R 4 /R 5 , may be interconnected. Further, the invention relates to methods for the synthesis of chiral phosphorus compounds of general formula (I) and their use as catalyst components in processes for the preparation of optically active products.

The present invention relates to novel chiral phosphorus compounds thatcan be readily prepared from quinoline derivatives, and their use ascatalysts or catalyst components in processes for the preparation ofoptically active products.

Chiral phosphorus compounds are of great interest as catalysts orcatalyst components (“ligands”) for the enantioselective chemicalsynthesis of optically active products (Handbook of EnantioselectiveCatalysis with Transition Metal Compounds, Vol. II, VCH, Weinheim,1993). Optically active products are of great economic importance asflavouring agents, cosmetics, plant protectants, food additives,pharmaceuticals, or in the preparation of high-tech materials, such asspecial plastics (Comprehensive Asymmetric Catalysis, Springer, Berlin,1999). To date, despite of the wide variety of known chiral phosphoruscompounds, only a few members have been put to use in industrialprocesses for the preparation of optically active products, because manyligands have serious disadvantages for technical applications. Manyligands, although exhibiting high enantioselectivities, form the desiredchiral products with too low activities or insufficient chemo- orregioselectivities. Further, chiral phosphorus compounds which act asefficient ligands are often available only by tedious syntheses usingexpensive starting materials. In most efficient ligands, the chiralinformation which results in the selective formation of the opticallyactive products is based on the use of chiral building blocks which areeither derived from naturally occurring compounds or otherwisecommercially available in an optically pure form. A structural variationin the chiral centre for optimising the phosphorus compound cannot berealized in a simple way in this case, and often only one of the twopossible configurations is available. Therefore, there is a great needfor novel chiral phosphorus compounds which can be synthesized in asimple and flexible way from readily available and inexpensive startingcompounds and can be effectively employed as catalysts or catalystcomponents for the preparation of chiral products in various types ofreaction.

U.S. Pat. No. 6,720,281 describes novel phosphorus compounds derivedfrom quinoline derivatives. These ligands are effective in manycircumstances, however the remains a need to provide alternativequinoline-based compounds that may be used in asymmetric catalysts.

The present invention relates to a novel class of chiral phosphoruscompounds of general formula (I)

wherein R¹, R², R³, R⁴, R⁵ are chiral or achiral organic residues whichare derived from substituted or unsubstituted straight or branched chainor cyclic aliphatic or aromatic groups and which, in the case of thepairs R¹/R² and R⁴/R⁵, may be interconnected. These compounds can beprepared simply and in few steps from derivatives of quinoline asinexpensive starting materials. The chiral information in the 2-positionof the quinoline skeleton, which is critical to the selective formationof the desired optically active products, is produced during thesynthesis and can be easily varied by selecting R³. The two isomers withthe different configurations in the 2-position can be effectivelyseparated from each other. The compounds of formula (I) can be employedas efficient catalysts or catalyst components in the preparation ofoptically active products, wherein high activities and selectivities areachieved especially in enantioselective hydroformylation andhydrogenation.

The synthesis of compound (I) can be accomplished by a variety ofsynthetic approaches. In one embodiment, the synthesis of compounds (I)may proceed via the “Quinaphos” compounds (VI). Synthesis of the“Quinaphos” compounds (VI) may conveniently start from8-phosphinoquinolines (II) as follows; (see Scheme 1).

It will be understood that, in the depictions herein, where R³ isconnected by a curly line (˜) both enantiomers may be present. Compounds(II) are already known and different residues R¹ and R² and can beeasily prepared on a multigram scale via different routes (typicalexamples: Inorg. Chem. 1982, 21, 1007; J. Organomet. Chem. 1997, 535,183). By means of these syntheses and suitable simple modifications,compounds of formula (II) can be prepared in which R¹ or R² are the sameor different chiral or achiral organic residues which are derived fromsubstituted or unsubstituted straight or branched chain or cyclicaliphatic or aromatic groups and may be interconnected. Residues R¹ andR² can be independently selected from the groups methyl, ethyl,n-propyl, i-propyl, n-butyl, t-butyl, hexyl, F(CF₂)_(m)(CH₂)_(n)—(m=1-10, n=0-4), cyclo-hexyl, menthyl, allyl, benzyl, CH₃O(CH₂)₂OCH₂—,phenyl, tolyl, anisyl, trifluoro-methylphenyl, F(CF₂)_(m)(CH₂)_(n)C₆H₄—(m=1-10, n=0-4), bis(trifluoromethyl)phenyl, chlorophenyl,pentafluorophenyl, hydroxyphenyl, carboxyphenyl, NaO₃SC₆H₄—, naphthyl,fluorenyl, pyridyl or furyl, the groups mentioned not being intended toimply any limitation to the scope of application. When the two groupsare interconnected, there may be formed substituted or unsubstitutedchiral or achiral bridges which are derived, for example, from theskeletons —(CH₂)_(n)— (n=2-4), —CH(CH₃)CH(CH₃)—, —CH(CH₃)CH₂CH(CH₃)—,1,1′-bipheny-2,2′-diyl or 1,1′-binaphth-2,2′-diyl, again no limitationbeing implied by this listing.

The reaction of compound (II) with nucleophilic reagents R³M yieldscompounds (III), wherein R³ refers to the same definition as R¹ or R².The addition in 2-position of the quinoline can be accomplished withGrignard compounds (M=MgHal, Hal=halogen) and many other organometalliccompounds (e.g., M=Li, ZnR, SnR₃, SiR₃; R=alkyl or aryl residue), sothat a wide variety of possible derivatives results. The addition in2-position of the quinoline produces a chiral centre, thestereochemistry at this centre not being defined in the absence of anadditional chiral auxiliary or catalyst. In the presence of a chiralauxiliary or catalyst, the addition of R³M may performed in anenantioselective manner (e.g. see F. Amiot, L. Cointeaux, E. J. Silve,A. Alexakis Tetrahedron 2004, 60, 8221-8231; L. Cointeaux, A. AlexakisTetrahedron: Asymmetry 2005, 16, 925-929). Enantioselective addition maybe achieved also using chiral reagents (see e.g. R. Yamaguchi, M.Tanaka, T. Matsuda, T. Okano, T. Nagura, K. Fujita Tetrahedron Letters2002, 43, 8871-8874).

Compounds (III) may be converted to the 1,2-dihydroquinoline derivatives(IV) by hydrolysis using e.g. water or aqueous acid. Reaction withchlorophosphinites (R⁴O)(R⁵O)PCl in the presence of bases such astriethylamine or pyridine yields the desired phosphorus compounds offormula (VI). An alternative approach depicted above is the reaction ofcompound (III) with PCl₃ to form the dichlorophosphine derivatives (V).A further approach, not depicted, is the reaction of compound (III) withP(NEt₂)₂Cl or P(NMe₂)₂Cl to form the bis(di-ethylamino)phosphine orbis(di-methylamino)phosphine derivatives, respectively, which uponreaction with alcohols or diols again yields compounds (VI). Compounds(III) can also be reacted directly with chloro-phosphinites(R⁴O)(R⁵O)PCl without further addition of bases to (VI).

The residues R⁴ and R⁵ may be the same or different, achiral or chiral,and may be interconnected. Otherwise, the residues have the samedefinition as residues R¹ and R². Examples of alcohols and diols whichmay be used for the preparation of the corresponding compounds(R⁴O)(R⁵O)PCl or directly reacted with compounds (V) include methanol,ethanol, iso-propanol, benzyl alcohol, cyclohexanol, allyl alcohol,phenol, methylphenol, chlorophenol, naphthol, furfurol, ethylene glycol,1,3-propanediol, 1,3-pentanediol, cyclohexanediol, glycerol,monosaccharides, oligosaccharides, catechol,2,2′-dihydroxy-1,1′-biphenyl,3,3′,5,5′-tetra-tert-butyl-2,2′-dihydroxy-1,1′-biphenyl,3,3′-di-tert-butyl-2,2′-dihydroxy-5,5′-dimethoxy-1,1′-biphenyl,5,5′-dichloro-4,4′,6,6′-tetramethyl-2,2′-dihydroxy-1,1′-biphenylor 2,2′-dihydroxy-1,1′-binaphthyl, the listing not being intended toimply any limitation to the scope of application.

When optically active (R⁴O)(R⁵O)P groups are used, compounds (VI) areobtained as diastereomers which can be separated by crystallization,chromatography or other suitable separation methods. Alternatively, theseparation of the two stereoisomers can be effected on the stage of the1,2-dihydroquinoline derivatives (IV), which can be resolved byconventional methods into enantiomers (IVa) and (IVb) (see, for example,Tetrahedron Asymmetry 1999, 10, 1079).

In one embodiment, synthesis of (I) may be by hydrogenation of a1,2-dihydroquinoline ring (see Scheme 2).

Hence compounds of formula (I) may be prepared from the “Quinaphos”compounds (VI) by selective hydrogenation of the double bond in thedihydroquinoline ring in the presence of known heterogeneoushydrogenation catalysts, e.g. palladium, platinum, rhodium, ruthenium,iridium supported on carbon, alumina, silica etc. Suitable catalysts aredescribed in the Johnson Matthey Technical Handbook 2005. Alternativelyhydrogenation may be accomplished using homogeneous hydrogenationcatalysts that are known to reduce carbon-carbon double bonds, such asiridium complexes bearing phosphine-oxazoline ligands, Crabtreecatalyst, rhodium complexes bearing ferrocenyl and paracylophane-baseddiphosphines etc. Suitable catalysts are described in X. Cui, K. BurgessChem. Rev. 2005, 105, 3272. Heterogeneous catalysts of palladium may beparticularly suited to achieve the desired transformation. Allabove-mentioned hydrogenation procedures may require the protection ofthe phosphine and phosphoramidite groups e.g. as the correspondingBH₃-derivatives. Compounds (I) are then obtained after removal of theBH₃ protecting groups e.g. with an amine.

Alternatively, the selective hydrogenation of the carbon-carbon doublebond of the dihydroquinoline ring may be applied to intermediatecompound (IV). The resulting compound (X) may be easily transformed intocompound (I) by the same procedure used to prepare “Quinaphos” compound(VI).

Accordingly the invention further provides the intermediate chiralphosphorus compound of formula (X):

wherein R¹, R², R³ are chiral or achiral groups selected from the listconsisting of substituted or unsubstituted straight-chain,branched-chain or cyclic aliphatic or aromatic groups and in which thepair R¹/R² may be interconnected to form a ring.

The selective hydrogenation of the carbon-carbon double bond of the1,2-dihydroquinoline ring can also be performed on intermediates (VIII),prepared from starting material (VII), bearing in position 8 of thedihydroquinoline ring a group X that is a precursor of the phosphinesubstituent (such as bromide, chloride, iodide, hydroxy, alkoxy,trifloromethylsulphonyloxy etc). Compounds (VII) are readily availableor may be synthesized from quinoline using known methods. Thetransformation of compounds (VIII) and (IX) into compounds (IV) and (X)respectively, may require the protection of the secondary amine bystandard methods before the phosphine group R¹R²P— is introduced inposition 8 via a sequence of lithiation and reaction with theappropriate chloro-phosphine electrophyle or via coupling with anappropriate phosphorus containing compound in the presence of atransition metal catalyst. For example, Pd or Ni-catalysed coupling withsecondary phosphines is described in A. Stadler, C. O. Kappe Org. Lett2002, 4, 3541; D. Cai et al. J. Org. Chem. 1994, 59, 7180; J. Xiao etal. Tetrahedron 2004, 60, 4159; copper catalysed coupling with secondaryphosphines and phosphates is described in D. Gelman, L. Jiang, S. L.Buchwald: Org. Lett. 2003, 5, 2315; D. Van Allen, D. Venkataraman J.Org. Chem. 2003, 68, 4590; and nickel catalysed coupling withchlorophosphines is described in S. Lanemann et al. Chem. Commun. 1997,2359; and references therein.

The selective hydrogenation of the carbon-carbon double bond of the1,2-dihydroquinoline ring does not affect the obtainment ofenantiomerically enriched compound (Ia) and (Ib) since the resolution ofracemic (I) can be achieved at any stage of the synthetic pathways heredescribed. The residue R³, in this route, may be introduced bynucleophilic addition to the quinoline ring as previously disclosed inthe aforesaid U.S. Pat. No. 6,720,281.

In an alternative embodiment, synthesis of the compound of formula (I)may be by asymmetric hydrogenation of the quinoline ring (see Scheme 3).Hence quinolines (XII) can be selectively hydrogenated in the presenceof homogeneous transition metal, particularly iridium, hydrogenationcatalysts bearing one or more chiral ligands, such as diphosphine orphosphorus-nitrogen ligands, and iodine to produce enantiomericallyenriched intermediates (Xa) or (Xb). A suitable method is disclosed byW-B. Wang, S-M. Lu, P-Y. Yang, X-W. Han, Y-G. Zhou J. Am. Chem. Soc.2003, 125, 10536 and W. H. Lam, S. Chan, W.-Y. Yu, Y.-M. Li, R. Guo, Z.Zhou, A. S. C. Chan J. Am. Chem. Soc. 2006, 128, 5955-5965.

It is possible that the phosphine group in position 8 of the quinolinemay interact with the homogeneous transition metal catalyst and thatthis interaction may, in some cases, inhibit the hydrogenation. To avoidthis problem the asymmetric hydrogenation may be performed onintermediates (XI) bearing in position 8 of the dihydroquinoline ring agroup X that is a precursor of the phosphine substituents (such asbromide, chloride, iodide, hydroxy, alkoxy, trifloromethylsulphonyloxyetc). The resulting compounds (IXa) and (IXb) may be transformed intocompound (I) by via known synthetic transformations. Alternatively, theinterference of phosphine group in the intermediate (XII) during thehydrogenation may be avoided by transforming it into the correspondingoxide or protecting it as BH₃-adduct. After partial hydrogenation of thequinoline ring, reduction of the phosphine oxide group back to phosphinegroup using known procedures (e.g. with trichlorosilane) or treatment ofthe BH₃-adduct with an amine, generates compounds (IXa) and (IXb).

In alternative to metal catalysed hydrogenation, enantioselectiveBrønsted acid catalysed transfer hydrogenation may be also used asreported by M. Rueping, A. P. Antonchick, T. Theissmann Angew. Chem.Int. Ed. 2006, 45, 3683-3686.

This synthetic approach has the advantage of fixing the stereogeniccenter in position 2 without the need of the resolution of racemic (I)or any of the intermediates leading to (I). Another advantage of thisroute is that the residue R³ is already present in the quinoline ring.Quinolines (XI) substituted in position 2 can be prepared by a varietyof methods such as the Skraup-Doebner-Von Miller quinoline synthesis(review: N. L. Allinger, G. L. Wang, B. B. Dewhurst J. Org. Chem. 1974,12, 1730; S. E. Denmark, S. Venkatraman J. Org. Chem. 2006, 7, 1668) andFriedlander reaction. New efficient iridium and ruthenium catalysedcyclisation reactions to form 2-substituted quinolines have recentlybeen reported in the literature (K. Taguchi, S. Sakaguchi, Y. IshiiTetrahedron Letters 2005, 4539 and references therein). Compounds (VIII)and (IX) may be synthesised from readily available aniline compounds asfollows; (see Scheme 4).

The acyclic intermediates (XIV) may be readily synthesised fromcompounds (XIII) using a R³-functional carboxylic acid, ester orchloride of formula R⁷OCHR³CH₂COOR⁶ in which R⁶ may be H, Cl or C1-C10alkyl (aliphatic, branched or cyclic, including benzyl) and R⁷ may beC1-C10 alkyl (aliphatic, branched or cyclic, including benzyl), Tosyl,Mesyl, Triflate, Acetyl, H or a silyl protecting group such as TMS. Thecyclisation to (XV) may be accomplished by standard transformations.Compound (XV) may be reduced to a benzylic alcohol (XVI) that will giveintermediates (VIII) and (IX) using steps of elimination/hydrogenationor hydrogenolysis of benzylic alcohol. Aromatic ketones can behydrogenated to the corresponding alcohols in the presence of a varietyof heterogeneous catalysts (for example, palladium on carbon, JohnsonMatthey Technical Handbook 2005) or homogeneous catalysts (for example,ruthenium or rhodium or iridium complexes) with both hydrogen gas orhydrogen donors such as formic acid, sodium formate etc, (JohnsonMatthey Technical Handbook 2005, R. Noyori, T. Ohkuma Angew. Chem. Int.Ed. 2001, 40, 40; T. Ikariya, K. Murata, R. Noyori Org. Biomol. Chem.2006, 4, 393). Hydrogenolysis in the presence of heterogeneoushydrogenation catalysts is favoured by acid conditions, elevatedtemperatures and protic solvents and will lead directly to compound (IX)without any need of isolating intermediate (VIII).

Intermediates (VIII) and (IX) may be transformed into compound (I) viaknown synthetic transformations (for example, as described in J. MarchAdvanced Organic Chemistry, Wiley 1992.

Compounds (Ia) and (Ib) can then be obtained in enantiomerically pureform by resolution of any of the intermediates.

Scheme 5 describes an alternative synthesis based on the concept ofbuilding the tetrahydroquinoline ring.

This approach makes use of intermediates (XVIII) or (XXI) where a chiralauxiliary, preferably a chiral amine of formula H₂NCH(CH₃)Ar, in whichAr is an aryl group, such as 2-phenyl-ethylamine, 2-naphtylethylaminehas been introduced by coupling on the readily available startingmaterials (XVII) or (XX). By the term “aryl” we include phenyl, naphthyland substituted phenyl and naphthyl compounds, such as tolyl or xylyl.In compounds (XVII) and (XX) X may be selected from bromide, chloride,iodide, hydroxy, alkoxy, tosylate, mesylate, nonaflate, fluoride ortriflate and Y may be selected from fluoride, chloride, bromide, iodide,tosyl, mesyl, triflate, nonaflate etc. By using Buchwald-Hartwigcoupling chemistry (e.g. see J. F. Hartwig et al. J. Org. Chem. 1999,64, 5575; S. W. Buchwald et al. J. Org. Chem. 2000, 65, 1158; S. L.Buchwald et al. J. Org. Chem. 2000, 65, 1144) enantiomerically pureamines can be coupled with aryl-halides and triflates, tosylates,mesylates etc., without loss of enantiomeric purity. Alternatively, thedesired compounds may be obtained via Ulmann coupling (e.g. see D. Ma etal. Org. Lett. 2003, 5, 2453).

Compounds (XVIII) or (XXI) may be added to a suitable unsaturated esterwith high diatereoselectivity, preferably of formula R³CH═CHCOOR⁶, inwhich R6 is H, Cl or C1-C10 alkyl, preferably C1-10 alkyl. (This methodis described for example in S. G. Davies, O. Ichihara Tetrahedron:Asymmetry 1996, 7, 1919). In this case, this procedure may set in placethe stereogenic centre in position 2 in high enantiomeric purity

Intermediates (XIX) and (XXII) may be transformed into compounds (X) and(I) (here Xb and Ib) via known synthetic transformations. TheN-debenzylation may be achieved in one vessel using the sameheterogeneous hydrogenation catalysts employed for the reduction of theketone and hydrogenolysis of derived benzylic alcohol. Alternatively,different catalysts may be employed. Acidic solvents such as acetic acidor buffered solvents are desirable to prevent inhibition of thecatalyst.

Alternatively, as described in Scheme 6, starting materials (XVII) or(XX) can be coupled with enantiomerically pure β-aminoesters. (Asuitable method is described in D. Ma, C. Xia Org. Lett. 2001, 3, 2583).

In this case, the desired stereochemistry of position 2 is obtained bythe use of readily available enantiomerically pure synthons such asβ-aminoesters and acids, preferably of formula H₂NCHR³CH₂COOR⁶ in whichR⁶ may be H or C1-10 alkyl. The resulting enantiomerically purecompounds (XIVa), (XIVb), (XXIIIa) and (XXIIIb) may be cyclised andreduced to the dehydroquinoline following known chemicaltransformations.

Enantiomerically pure intermediates (X) or (IX) can be synthesisedstarting from (XXIV) or (XXVII) as shown in Scheme 7 (for (IXb) and(Xb)) and then further converted to (I) as described in Scheme 3. Thereaction sequence is based on a report of C. Theeraladanon, M. Arisawa,M. Nakagawa, A. Nishida Tetrahedron: Asymmetry 2005, 16, 827-831. Thisincludes a Mitsunobu coupling of (XXIV) or (XXVII) with readilyavailable enantiomerically pure allylic alcohols to form compounds (XXV)and (XXVIII), respectively, followed by a ring closing metathesis (RCM)to yield (XXVI) and (XXIX), respectively. Reduction of the C═C doublebond (described in Scheme 2) and cleavage of the tosyl group givesaccess to (IX) and (X) from (XXVI) and (XXIX), respectively. In somecases, could be more convenient to perform the last two steps ininverted order, i.e. before the cleavage of the tosyl group and thenreduction of the C═C double bond. Compounds (IX) may be phosphorylatedas shown in Scheme 3 or alternatively, compounds (XXVI) may bephosphorylated to form compounds (XXIX).

Accordingly, the invention further provides a method for preparing acompound of formula (I) as defined herein, comprising the step ofselectively hydrogenating a compound of formula (VI) to hydrogenate thecarbon-carbon double bond in the dihydroquinoline ring.

The invention further provides a method for preparing a compound offormula (I) as defined herein, comprising the step of reacting acompound of formula (X) with (R⁵O)(R⁴O)PCl.

Compound (X) may be prepared by selectively hydrogenating a compound offormula (IV) to hydrogenate the carbon-carbon double bond in the1,2-dihydroquinoline ring

Alternatively, compound (X) may be prepared by selectively hydrogenatinga compound of formula (VIII), in which X is a group selected frombromide, chloride, iodide, hydroxy, alkoxy, mesylate, tosylate,nonaflate or triflate, to hydrogenate the carbon-carbon double bond inthe dihydroquinoline ring to form a compound of formula (IX) andphosphorylating the compound of formula (IX) with a phosphorylatingcompound.

By “phosphorylating compound” we mean those phosphorus compounds able todisplace X with the R¹R²P— moiety.

Alternatively compound (X) may be made in enantiomerically enriched formby asymmetrically hydrogenating a compound of formula (XII) in thepresence of a homogeneous transition metal hydrogenation catalyst havingone or more chiral ligand to produce enantiomerically enrichedintermediates of formula (Xa) or (Xb).

Compounds (Xa) or (Xb) may alternatively be prepared by asymmetricallyhydrogenating a compound of formula (XI), in which X is a group selectedfrom bromide, chloride, iodide, hydroxy, alkoxy, mesylate, tosylate,nonaflate or triflate, in the presence of a homogeneous transition metalhydrogenation catalyst having one or more chiral ligand to produceenantiomerically enriched intermediates (IXa or IXb), and reactingintermediates (IXa) or (IXb) with a phosphorylating compound.

Compounds (Xa) or (Xb) may alternatively be prepared by hydrogenating aketone compound of formula (XXII).

Compounds (Xa) or (Xb) may alternatively be prepared by;

-   (i) performing a ring closing metathesis on compounds of formula    (XXVb) or (XXVa) to form compounds (XXVIb) or (XXVIa), respectively,-   (ii) cleaving the tosyl group to form compounds (VIIIb) or (VIIIa)    respectively,-   (iii) hydrogenating compounds (VIIIb) or (VIIIa) to form compounds    (IXb) or (IXa) respectively, and-   (iv) phosphorylating compounds (IXb) or (IXa) with a phosphorylating    compound to form compounds (Xb) or (Xa), respectively. Steps ii, iii    and iv may be performed in different order.

Compounds (Xa) or (Xb) may alternatively be prepared by;

-   (i) performing a ring closing metathesis of compounds of formula    (XXVIIIb) or (XXVIIIa) to form compounds (XXIXb) or (XXIXa),    respectively,-   (ii) cleaving the tosyl group to form compounds (IVb) or (IVa),    respectively, and-   (iii) hydrogenating compounds (IVb) or (IVa), to form compounds (Xb)    or (Xa), respectively. Steps ii and iii may be performed in reverse    order.

The chiral phosphorus compounds (I) can be used in an optically pureform, as a mixture of diastereomers or in the form of the purediastereomers as effective catalysts or catalyst components in thesynthesis of optically active products. Particularly preferred aresyntheses in which compounds of formula (I) are employed as components(“ligands”) of transition metal catalysts. Such catalysts contain one ormore transition metal centres which may be the same or different.Preferred metals include Cu, Ag, Au, Ni, Pd, Pt, Co, Rh, Ir, Fe, Ru, Os,Mn, Re, Cr, Mo, W, Ti or Zr. Particularly preferred are Cu, Ni, Pd, Pt,Rh, Ir or Ru.

The catalysts may be employed in the form of isolated compounds whichalready contain the metal and the ligand (I), or may be formed in situfrom ligand (I) and suitable metal-containing components. As themetal-containing components, the metals themselves, simple salts orcomplex compounds of the corresponding metals can be used. The molarratio between the ligand (I) and the metal centre can be optimallyadapted for the respective reaction and is usually between 1:1 and 10:1.

The catalytic syntheses using the ligands (I) can be performed in eitherabsence or presence of a solvent, wherein the solvent can have apositive influence on activity or enantioselectivity, or can facilitatethe separation of the product and catalyst. As the solvent, typicalorganic solvents, such as benzene, toluene, methylene chloride, ethanol,methanol, tetrahydrofuran, diethyl ether, methyl, t-butyl ether or ionicliquids may be used. Water is also suitable as a solvent when the ligandis sufficiently soluble in water due to suitable polar substituents(e.g., COOH, NH³⁺, SO³⁻, see Angew. Chem. 1993, 105, 1588). Thereactions may also be performed in supercritical carbon dioxide as thesolvent if adequate solubility is ensured by suitable substituents(e.g., perfluoroalkyl residues, see PCT application WO 98/32533). Tofacilitate separation from the reaction products, the ligands (I) can bebound to solid supports using known methods (adsorption, inclusion,covalent bonding: Synthesis 1997, 1217).

Product from catalyst separation can be achieved by running thereactions under biphasic conditions (e.g see Multiphase HomogeneousCatalysis, Eds.: B. Cornils, W. A. Herrmann, D. Vogt, I. Horvath, H.Olivier-Bourbigon, W. Leitner, S. Mecking; Wiley-VCH, 2005) or byselectively extracting the products with an additional solvent after thereaction. The scope of application of ligands (I) includes asymmetricreductions (e.g., hydrogenation, transfer hydrogenation), asymmetriccarbon-carbon bond formation (e.g., hydroformylation, Heck coupling,allylic alkylation, hydrocyanation, hydrovinylation, polymerization) andasymmetric bond formation between carbon and heteroatoms (e.g.,hydroboration, hydrosilylation, hydroamination, hydrophosphination andhydrophosphorylation).

Enantioselective hydroformylation is an efficient method for thesynthesis of chiral, non-racemic aldehydes from olefins (CatalyticAsymmetric Synthesis, Ed.: I. Ojima, VCH, Weinheim, 1993, pages 273ff).This type of reaction has met with great interest especially as apossible approach to chiral building blocks for the production offlavouring agents, cosmetics, plant protectants, food additives(vitamins) and pharmaceuticals (Chirality 1991, 3, 355). In particular,there may be mentioned the preparation of the anti-inflammatory andanalgesic drugs ibuprofen and naproxen by oxidation of the correspondingaldehydes, which can be obtained from vinyl arenes by means ofenantioselective hydroformylation. In addition to enantioselectivity, inthis reaction, chemoselectivity (side reaction is predominantlyhydrogenation) and regioselectivity in favour of the branched chiralaldehyde are of particular importance. Preferred catalysts for thehydroformylation are formed on the basis of the metals Fe, Co, Ir, Ru,Pt, Rh, more preferably on the basis of Pt and Rh. The molar ratio ofligand/metal should be between 1:1 and 10:1, preferably between 1:1 and4:1. The molar ratio of substrate and catalyst can be widely varied, andpreferably a ratio of between 100:1 and 10,000:1 may be used. The gaseshydrogen and carbon monoxide can be added to the reactor eitherseparately or as a mixture. The partial pressure of the individual gasesis within a range of from 1 to 100 bar. The total pressure of synthesisgas can be within a range of from 1 to 200 bar, preferably within arange of from 10 to 100 bar. The reaction temperature can be widelyvaried and is between −20° C. and 150° C., preferably between 20° C. and80° C.

Enantioselective hydrogenation is an efficient method for the synthesisof chiral, non-racemic organic compounds (Catalytic AsymmetricSynthesis, Ed.: I. Ojima, VCH, Weinheim, 1993, pages 1ff), which is ofgreat importance, in particular, to the preparation of biologicallyactive substances. Enantioselective hydrogenation is known for a widevariety of functional groups, especially for substrates with prochiralC═C, C═N or C═O double bonds. The hydrogenation of dehydroamino acids isan attractive approach to natural and non-natural amino acids and hasalready found a technical application, for example, in the preparationof L-Dopa, a medicament against Parkinson's disease (Topics in Catalysis1998, 5, 3). Preferred catalysts for hydrogenation with ligands of thepresent invention are formed on the basis of the metals Pd, Pt, Co, Ir,Rh and Ru. The molar ratio of ligand/metal should be between 1:1 and10:1, preferably between 1:1 and 2.5:1. The molar ratio of substrate andcatalyst can be widely varied and is preferably between 100:1 and100,000:1. The partial pressure of hydrogen during hydrogenation shouldbe within a range of from 0.3 to 200 bar, preferably between 10 and 100bar. The reaction temperature can be widely varied and is between −20°C. and 150° C., preferably between 20° C. and 60° C.

In transfer hydrogenation a hydrogen donor such as isopropanol or formicacid may be used with catalysts of the type [(sulphonylated diamine)RuCl (arene)] for the reduction of carbonyl groups. Phosphoruscompound-containing catalysts according to the present invention mayalso be used. This technology provides a powerful complement tocatalytic asymmetric hydrogenation. Transfer hydrogenation, in fact, isparticularly suitable for the asymmetric reduction of ketones that aredifficult substrates for hydrogenation, such as acetylenic ketones andcyclic ketones.

Enantioselective hydroboration is a typical example of a reaction withformation of a carbon-heteroatom bond. It has met with great interestsince the boranes produced are interesting intermediates for furthersyntheses (e.g., formation of chiral alcohols, carbon-carbon bondformation, etc.) (Tetrahedron 1997, 53, 4957). In addition to theenantioselectivity of the carbon-boron bond formation, chemoselectivity(side reaction is predominantly reduction) and regioselectivity are alsoimportant characteristics of this reaction. Preferred catalysts for thehydroboration with ligands (I) are formed on the basis of Rh. The molarratio of ligand/metal should be between 1:1 and 4:1, preferably between1:1 and 2:1. The molar ratio of substrate and catalyst can be widelyvaried and is preferably between 100:1 and 10,000:1. The reactiontemperature can be widely varied and is between −80° C. and 100° C.,preferably between 20° C. and 80° C.

The invention is further illustrated by reference to the followingExamples.

Anhydrous solvents were purchased from Fluka and used as received inSureSeal™ bottles over molecular sieves. All reagents were purchasedfrom commercial sources and used without further purification.

EXAMPLE 1 Preparation of8-Diphenylphosphino-2-methyl-1,2,3,4-tetrahydroquinoline (7)

(a) synthesis of 8-Diphenylphoshinoquinoline (1)

To a stirred solution of 8-bromoquinoline (20.8 g, 100 mmol) in dry THF(200 mL) under nitrogen was added n-BuLi (62.5 mL, 1.6 M in hexanes, 100mmol) at −78° C. and the mixture was stirred for 30 minutes.Chlorodiphenylphosphine (17.9 mL, 100 mmol) was then added and thesolution was allowed to warm up to room temperature and stirred for 2 h.The solution was then cooled to −78° C. and quenched by addition ofsaturated aqueous NH₄Cl solution (100 mL). After warming up to roomtemperature, the solution was filtered, the precipitated solidcollected, taken up in CH₂Cl₂ (200 mL) and filtered over silica geleluting with further portions of CH₂Cl₂ (4×200 mL). The combinedfiltrates were evaporated to give 1 as a light yellow solid (19 g, 60%yield). ¹H NMR (400.13 MHz, CDCl₃) δ 8.37 (dd, 1H, J=4.0, 1.6 Hz, C²—H),8.17 (dd, 1H, J=8.0, 1.6 Hz, C³—H), 7.82 (d, 1H, J=8.4 Hz, C⁵—H), 7.44(t, 1H, J=7.6 Hz, C⁶—H), 7.40 (dd, 1H, J=8.0, 4.0 Hz, C⁴—H), 7.3-7.2 (m,10H, Ph-H), 7.14 (ddd, 1H, J=7.2, 3.6, 1.6 Hz, C⁷—H) ppm; ¹³C NMR(100.61 MHz, CDCl₃) δ 149.8, 149.6 (d, J=17.2 Hz), 138.4 (d, J=12.1 Hz),137.4 (d, J=11.1 Hz), 136.2, 134.4, 134.2 (d, J=21.2 Hz), 128.8, 128.4(d, J=19.2), 127.9, 126.57, 121.41 ppm; ³¹P NMR (161.97 MHz, CDCl₃) δ15.0 ppm.

b) Synthesis 8-Diphenylphosphino-2-methyl-1,2-dihydroquinoline (2)

To a stirred solution of 8-diphenylphoshinoquinoline (1) (10 g, 31.95mmol) in dry THF (150 mL) under nitrogen was added MeLi (39.9 mL, 1.6 Min diethyl ether, 1 mmol) at −78° C. and the solution was stirred at 0°C. for 10 minutes. The solution was cooled down to −78° C., saturatedaqueous NH₄Cl solution (100 mL) was added and the mixture was warmed toroom temperature. Products were extracted with EtOAc, washed with waterand saturated aqueous NaCl, dried (MgSO₄) and evaporated to give 2 as ayellow oil, which solidified on standing (10.5 g, quantitative). ¹H NMR(400.13 MHz, CDCl₃) δ 7.4-7.25 (m, 10H, Ph-H), 6.86 (dd, 1H, J=7.2, 1.2,C⁵—H), 6.63 (ddd, 1H, J=7.6, 6.0, 1.6 Hz, C⁷—H), 6.49 (t, 1H, J=7.6 Hz,C⁶—H), 6.29 (d, 1H, J=9.6 Hz, C⁴—H), 5.54 (ddd, 1H, J=10.0, 4.0, 2.0 Hz,C³—H), 4.71 (d, 1H, J=7.6 Hz, N¹—H), 4.35 (m, 1H, C²—H), 1.15 (d, 3H,J=6.4 Hz, C^(1'), —CH₃) ppm; ¹³C NMR (100.61 MHz, CDCl₃) δ 147.0 (d,J=18.2 Hz), 135.5 (d, J=13.1 Hz), 135.4 (d, J=12.1 Hz), 134.2 (d, J=5.1Hz), 133.4 (d, J=18.2 Hz), 133.3 (d, J=18.2 Hz), 128.5 (d, J=11.1 Hz),128.4 (d, J=12.1 Hz), 128.0, 117.0, 116.1, 48.2, 24.2 ppm; ³¹P NMR(161.97 MHz, CDCl₃) δ −23.2 ppm.

c) Conversion of (2) to8-Diphenylphosphinoyl-2-methyl-1,2-dihydroquinoline (5)

To a solution of 8-diphenylphosphino-2-methyl-1,2-dihydroquinoline (2)(10.5 g, 32 mmol) in CH₂Cl₂ (100 mL) was added H₂O₂ (6.6 mL, 30% w/w inH₂O, 63.9 mmol) at 0° C. and the solution was stirred at roomtemperature for 1 hour. The solution was then cooled to 0° C., saturatedaqueous Na₂SO₃ solution (10 mL) was added and the mixture was warmed toroom temperature. Products were extracted with EtOAc, washed with waterand saturated aqueous NaCl, dried (MgSO₄) and evaporated to give 5 as ayellow oil (11 g, quantitative). ¹H NMR (400.13 MHz, CDCl₃) δ 7.7-7.6(m, 4H, Ph-H), 7.6-7.5 (m, 2H, Ph-H), 7.5-7.4 (m, 4H, Ph-H), 6.97 (bs,1H, N¹—H), 6.87 (d, 1H, J=7.2 Hz, C⁵—H), 6.55 (ddd, 1H, J=14.0, 8.0, 1.6Hz, C⁷—H), 6.36 (ddd, 1H, J=10.0, 7.6, 2.8 Hz, C⁶—H), 6.22 (d, 1H,J=10.0 Hz, C⁴—H), 5.51 (ddd, 1H, J=10.0, 4.0, 2.0 Hz, C³—H), 4.43 (m,1H, C²—H), 1.17 (d, 3H, J=6.8 Hz, C^(1'), —CH₃) ppm; ¹³C NMR (100.61MHz, CDCl₃) δ 148.2 (d, J=5.1 Hz), 146.0 (d, J=6.1 Hz), 135.7 (d, J=8.1Hz), 134.8, 132.4, 131.3 (d, J=5.1 Hz), 131.0 (d, J=11.1 Hz), 130.8 (d,J=10.1 Hz), 130.7 (d, J=10.1 Hz), 130.1, 129.2, 127.2 (d, J=12.1 Hz),126.6 (d, J=13.1 Hz), 126.3, 125.0 (d, J=8.1 Hz), 124.1 (d, J=13.1 Hz),122.8, 121.1, 119.7 (d, J=8.1 Hz), 113.6 (d, J=14.1 Hz), 107.3, 106.2,46.9, 23.5 ppm; ³¹P NMR (161.97 MHz, CDCl₃) δ 36.0 ppm.

d) Conversion of (5) to8-Diphenylphosphinoyl-2-methyl-1,2,3,4-tetrahydroquinoline (6)

A suspension of 8-diphenylphosphinoyl-2-methyl-1,2-dihydroquinoline (5)(11 g, 32 mmol) and Pd/C (1.1 g, 10 wt %) in MeOH (40 mL) was stirredunder H₂ at 145 psi pressure for 16 hours. The mixture was then dilutedwith EtOAc (200 mL) and filtered over celite (−25 mL). The filtrate wasthen evaporated to give compound 6 as a yellow oil (11.2 g,quantitative). ¹H NMR (400.13 MHz, CDCl₃) δ 7.7-7.6 (m, 4H, Ph-H),7.6-7.5 (m, 2H, Ph-H), 7.5-7.4 (m, 4H, Ph-H), 7.03 (d, 1H, J=7.2 Hz,C⁵—H), 6.87 (bs, 1H, N¹—H), 6.58 (dd, 1H, J=14.0, 7.2 Hz, C⁷—H), 6.39(ddd, 1H, J=10.4, 7.2, 2.8 Hz, C⁶—H), 3.5-3.4 (m, 1H, C²—H), 2.8-2.7 (m,2H, C⁴—H), 1.9-1.8 (m, 1H, C^(3a)—H), 1.6-1.4 (m, 1H, C^(3b)—H), 1.13(d, 3H, J=6.4 Hz, C^(1′)—CH₃) ppm; ¹³C NMR (100.61 MHz, CDCl₃) δ 148.9,132.0 (d, J=11.1 Hz), 131.5, 131.0 (d, J=10.1 Hz), 130.7 (d, J=10.1 Hz),130.6 (d, J=10.1 Hz), 130.4 (d, J=6.1 Hz), 130.3 (d, J=6.1H), 130.1 (d,J=11.1 Hz), 127.0 (d, J=13.1 Hz), 126.9 (d, J=12.1 Hz), 120.4 (d, J=8.1Hz), 112.5 (d, J=14.1 Hz), 107.9, 106.9, 45.4, 27.4, 25.5, 20.9 ppm; ³¹PNMR (161.97 MHz, CDCl₃) δ 36.4 ppm.

e) Conversion of (6) to8-Diphenylphosphino-2-methyl-1,2,3,4-tetrahydroquinoline (7)

To a solution of8-diphenylphosphinoyl-2-methyl-1,2,3,4-tetrahydroquinoline (6) (1.5 g,4.5 mmol) in dry degassed toluene (40 mL) was added degassed Et₃N (3.15mL, 22.5 mmol) followed by trichlorosilane (2.25 mL, 22.5 mmol). Themixture was stirred at 80° C. for 30 minutes before cautiously adding 2NNaOH (150 mL) and cooling down to room temperature. Products were thenextracted with EtOAc, washed with water and saturated aqueous NaCl,dried (MgSO₄) and evaporated to give a yellow oil. This oil was taken upin CH₂Cl₂ (100 mL), and filtered over silica gel (˜25 mL) eluting withfurther portions of CH₂Cl₂ (4×100 mL). The combined filtrates were thenevaporated to give compound 7 (1.2 g) as a light yellow oil in 80%yield. ¹H NMR (400.13 MHz, CDCl₃) δ 7.4-7.3 (m, 10H, Ph-H), 6.99 (d, 1H,J=7.2 Hz, C⁵—H), 6.62 (ddd, 1H, J=7.2, 6.0, 1.2 Hz, C⁷—H), 6.52 (t, 1H,J=7.6 Hz, C⁶—H), 4.65 (bs, 1H, N¹—H), 3.4-3.3 (m, 1H, C²—H), 2.9-2.7 (m,2H, C^(4a/b)—H), 2.0-1.9 (m, 1H, C^(3a)—H), 1.6-1.5 (m, 1H, C^(3b)—H),1.11 (d, 3H, J=6.4 Hz, C^(1′)—CH₃) ppm; ¹³C NMR (100.61 MHz, CDCl₃) δ147.9 (d, J=18.2 Hz), 147.7 (d, J=18.2 Hz), 136.1 (d, J=12.1 Hz), 136.0(d, J=13.1 Hz), 135.8 (d, J=13.1 Hz), 135.7 (d, J=13.1 Hz), 134.1-133.5(m), 132.5 (d, J=12.1 Hz), 132.4 (d, J=12.1 Hz), 130.5, (d, J=13.1 Hz),128.7-128.4 (m), 120.7 (d, J=12.1 Hz), 117.0, (d, J=12.1 Hz), 116.3 (d,J=12.1 Hz), 47.4, 39.6, 26.8, 22.4 ppm; ³¹P NMR (161.97 MHz, CDCl₃) δ−21.9 ppm.

The tetrahydroquinoline product 7 may be converted into a compound offormula (I) by reaction with a suitable oxychlorophosphite using e.g.the method in Example 4(b).

EXAMPLE 2 Preparation of8-Diphenylphosphino-2-phenyl-1,2,3,4-tetrahydroquinoline (3)

a) Synthesis of 8-Diphenylphosphino-2-phenyl-1,2-dihydroquinoline (4)

PhLi (0.56 mL, 1.8M in di-n-butyl ether, 1 mmol) was added to a stirredsolution of 8-diphenylphoshinoquinoline (1) (156 mg, 0.5 mmol) in dryTHF (5 mL) at −78° C. and the solution was stirred at 0° C. for 10minutes. The solution was then cooled to −78° C., saturated aqueousNH₄Cl solution (10 mL) was added and the mixture was warmed to roomtemperature. Products were extracted with EtOAc, washed with water andsaturated aqueous NaCl, dried (MgSO₄) and evaporated to give 4 (196 mg)quantitatively as a yellow oil. ¹H NMR (400.13 MHz, CDCl₃) δ 7.4-7.3 (m,15H, Ph-H), 6.92 (d, 1H, J=7.2 Hz, C⁵—H), 6.69 (ddd, 1H, J=7.2, 6.0, 1.2Hz, C⁷—H), 6.54 (t, 1H, J=7.2 Hz, C⁶—H), 6.38 (d, 1H, J=9.6 Hz, C⁴—H),5.64 (dd, 1H, J=10.0, 4.0 Hz, C³—H), 5.44 (bs, 1H, N¹—H), 5.15 (d, 1H,J=7.2 Hz, C²—H) ppm; ¹³C NMR (100.61 MHz, CDCl₃) δ 146.5 (d, J=19.2 Hz),145.1, 135.4 (d, J=8.1 Hz), 135.3 (d, J=7.1 Hz), 134.5, 133.7 (d, J=18.2Hz), 133.6 (d, J=19.2 Hz), 133.4 (d, J=19.2 Hz), 127.3, 128.7-128.3 (m),127.1, 126.0, 125.2, 124.5, 119.1, 117.1, 116.1 (d, J=8.1 Hz), 57.6 ppm;³¹P NMR (161.97 MHz, CDCl₃) δ-23.8 ppm.

b) Conversion of (4) to8-Diphenylphosphinoyl-2-phenyl-1,2-dihydroquinoline (8)

Following the procedure described for the synthesis of compound 5,8-diphenylphosphino-2-methyl-1,2-dihydroquinoline (4) (1.17 g, 3 mmol)was transformed into 8 (1.2 g) in 98% yield. ¹H NMR (400.13 MHz, CDCl₃)δ7.8-7.5 (m, 15H, Ph-H), 7.48 (bs, 1H, N¹—H), 7.03 (d, 1H, J=7.2 Hz,C⁵—H), 6.72 (ddd, 1H, J=9.2, 7.6, 1.2 Hz, C⁷—H), 6.51 (td, 1H, J=7.6,2.8 Hz, C⁶—H), 6.40 (dt, 1H, J=10.0, 1.6 Hz, C⁴—H), 5.73 (ddd, 1H,J=10.0, 4.4, 2.0 Hz, C³—H), 5.60 (dd, 1H, J=3.6, 1.6 Hz, C²—H) ppm; ¹³CNMR (100.61 MHz, CDCl₃) δ 148.2, 144.4, 132.0 (d, J=19.2 Hz), 131.9 (d,J=11.1 Hz), 131.2 (d, J=10.1 Hz), 131.1 (d, J=10.1 Hz), 131.0, 130.9,129.7, 127.8, 127.6 (d, J=12.1 Hz), 127.5 (d, J=12.1 Hz), 126.2, 124.9,124.7, 122.8, 119.1 (d, J=8.1 Hz), 114.0 (d, J=14.1 Hz), 108.3, 107.3,56.0 ppm; ³¹P NMR (161.97 MHz, CDCl₃) δ 34.9 ppm.

c) Conversion of (8) into 8-Diphenylphosphinoyl-2-phenyl-quinoline (9)

To a stirred solution of8-diphenylphosphinoyl-2-phenyl-1,2-dihydroquinoline (8) (1.2 g, 2.95mmol) in EtOAc (40 mL) was added Pd/C (1.2 g, 100 wt %) and thesuspension was stirred overnight at room temperature. The mixture wasthen filtered over celite and evaporated to give 9 (1.19 g)quantitatively as a white solid. ¹H NMR (400.13 MHz, CDCl₃) δ 8.63 (dd,1H, J=14.0, 7.2 Hz, C⁷—H), 8.16 (dd, 1H, J=8.8, 1.2 Hz, C⁵—H), 7.86 (1H,d, J=8.4 Hz, C³—H), 7.91 (dd, 4H, J=12.4, 7.2 Hz, Ph-H), 7.81 (dd, 1H,J=8.4 Hz, C⁴—H), 7.65 (td, 1H, J=8.0, 2.0 Hz, C⁶—H), 7.5-7.2 (m, 11H,Ph-H) ppm; ¹³C NMR (100.61 MHz, CDCl₃) δ 156.2, 147.4 (d, J=6.1 Hz),138.4, 137.7 (d, J=7.1 Hz), 136.8, 134.3, 133.2, 132.2, 132.1, 131.9,131.0, 129.3, 128.3, 128.0, 127.8, 127.4, 125.9, 125.7, 118.7 ppm; ³¹PNMR (161.97 MHz, CDCl₃) δ 27.7 ppm.

d) Conversion of (9) into8-Diphenylphosphinoyl-2-phenyl-1,2,3,4-tetrahydroquinoline (10)

Following the procedure previously described for the synthesis ofcompound 6, 8-diphenylphosphinoyl-2-phenyl-quinoline (9) (50 mg, 0.12mmol) was quantitatively transformed into compound 10 (51 mg). ¹H NMR(400.13 MHz, CDCl₃) δ 7.8-7.4 (m, 10H, Ph-H), 7.09 (bs, 1H, N—H), 7.08(1H, d, J=7.6 Hz, C⁵—H), 7.2-7.0 (3H, m, Ph-H), 7.0-6.9 (m, 2H, Ph-H),6.66 (ddd, 1H, J=14.4, 7.6, 1.2 Hz, C⁷—H), 6.47 (td, 1H, J=7.6, 3.2 Hz,C⁶—H), 4.57 (m, 1H, C²—H), 2.84 (m, 1H, C^(4a)—H), 2.63 (m, 1H,C^(4b)—H), 2.09 (m, 1H, C^(3a)—H), 1.84 (m, 1H, C^(3b)—H) ppm; ¹³C NMR(100.61 MHz, CDCl₃) δ 149.4 (d, J=4.1 Hz), 144.5, 133.1, 132.8,132.2-131-3 (m), 128.4, 128.2, 128.1, 126.7, 125.8, 121.8 (d, J=15.2Hz), 114.3 (d, J=16.2 Hz), 109.8, 55.2, 29.7, 26.1 ppm; ³¹P NMR (161.97MHz, CDCl₃) δ 35.5 ppm; HPLC (DAICEL-CHIRAPAK-AD, Hexane:IPA 60:40, 1mL/min, 25° C., 210 nm) τ₁=6.34, τ₂=8.91.

e) Conversion of (10) to8-Diphenylphosphino-2-phenyl-1,2,3,4-tetrahydroquinoline (3)

The product phosphine may be produced by treating compound (10)according to the method described for the conversion of compound (6)into compound (7).

The tetrahydroquinoline phosphine product may be converted into acompound of formula (I) by reaction with a suitable oxychlorophosphiteusing e.g. the method in Example 4(b).

EXAMPLE 3 Preparation of8-Diphenylphosphino-2-naphthalen-1-yl-1,2,3,4-tetrahydroquinoline (14)

a) Synthesis of8-Diphenylphosphino-2-naphthalen-1-yl-1,2-dihydroquinoline (11)

To a solution of 1-bromonaphthalene (8.57 mL, 60 mmol) in dry THF (100mL) under nitrogen was added n-BuLi (37.5 mL, 1.6 M in hexanes, 60 mmol)at −78° C. and the solution was stirred for 30 minutes at −78° C. beforeadding 8-diphenylphoshinoquinoline (1) (9.4 g, 30 mmol). After stirringat 0° C. for 10 minutes the solution was again cooled down to −78° C.,saturated aqueous NH₄Cl solution (10 mL) was added and the mixture waswarmed to room temperature. Products were then extracted with EtOAc,washed with water and saturated aqueous NaCl, dried (MgSO₄) andevaporated to give the 11 as a tan solid (13.0 g, 98%). ¹H NMR (400.13MHz, CDCl₃) δ 8.0-7.9 (m, 1H, C^(5′)—H), 7.8-7.7 (m, 1H, C^(8′)—H), 7.66(d, 1H, J=8.0 Hz, C^(2′)—H), 7.5-7.3 (m, 2H, C^(6′/7′)—H), 7.36 (d, 1H,J=6.4 Hz, C^(4′)—H), 7.3-7.1 (m, 11H, C^(3′)—H/Ph-H), 6.86 (dd, 1H,J=7.2, 1.2 Hz, C⁵—H), 6.64 (ddd, 1H, J=8.0, 6.4, 1.6 Hz, C⁷—H), 6.48 (t,1H, J=7.6 Hz, C⁶—H), 6.35 (dd, 1H, J=9.6, 1.6 Hz, C⁴—H), 6.16 (t, 1H,J=1.6 Hz, C²—H), 5.70 (ddd, 1H, J=10.0, 3.6, 1.6 Hz, C³—H), 5.02 (bd,1H, J=7.6 Hz, N—H) ppm; ¹³C NMR (100.61 MHz, CDCl₃) δ 146.6, 146.5,139.8, 129.5, 128.7, 128.6, 128.5, 128.4, 128.3 (m), 127.7, 135.1 (d,J=8.1 Hz), 134.9 (d, J=7.1 Hz), 134.5 (d, J=5.1 Hz), 133.9, 133.5 (d,J=13.1 Hz), 133.3 (d, J=12.1 Hz), 126.2, 125.6, 125.3, 125.2, 124.8,124.4, 122.5, 118.8, 117.1, 116.3, 54.0 ppm; ³¹P NMR (161.97 MHz, CDCl₃)δ −23.1 ppm.

b) Conversion of (11) into8-Diphenylphosphinoyl-2-naphthalen-1-yl-1,2-dihydroquinoline (12)

Following the procedure described for the synthesis of compound5,8-diphenylphosphino-2-naphthale-1-yl-1,2-dihydroquinoline (11) (8.8 g,20 mmol) in CH₂Cl₂ (60 mL) was oxidised with H₂O₂ (4.15 mL, 30% w/w inH₂O, 40 mmol) to give compound 12 (8.3 g) in 91% yield. ¹H NMR (400.13MHz, CDCl₃) δ 8.00 (d, 1H, J=8.4 Hz, C^(5′)—H), 7.83 (dd, 1H, J=7.6, 2.0Hz, C^(8′)—H), 7.7-7.6 (m, 3H, C^(2′)—H/Ph-H), 7.6-7.5 (m, 3H, Ph-H),7.5-7.4 (m, 5H, C^(6′/7′)—H/Ph-H), 7.4-7.3 (m, 2H, Ph-H), 7.29 (d, 1H,J=8.0 Hz, C^(4′)—H), 7.19 (t, 1H, J=8.0 Hz, C^(3′)—H), 6.96 (d, 1H,J=7.2 Hz, C⁵—H), 6.64 (ddd, 1H, J=13.6, 7.6, 1.2 Hz, C⁷—H), 6.44 (td,1H, J=7.2, 2.8 Hz, C⁶—H), 6.34 (dt, 1H, J=10.0, 1.6 Hz, C⁴—H), 6.32 (t,1H, J=1.6 Hz, C²—H), 5.78 (dd, 1H, J=10.0, 4.0 Hz, C³—H) ppm; ¹³C NMR(100.61 MHz, CDCl₃) δ 148.3, 148.2, 139.2, 132.9, 131.9 (d, J=11.1 Hz),131.8 (d, J=12.1 Hz), 131.2 (d, J=10.1 Hz), 130.9 (d, J=9.1 Hz), 130.7,129.8, 128.4, 127.8, 127.5 (d, J 12.1), 127.3 (d J 12.1), 126.6, 125.3,124.7, 124.5, 123.8, 123.7, 123.4, 121.5, 121.5, 118.9, 114.2, 114.0,108.9, 107.8, 52.6 ppm; ³¹P NMR (161.97 MHz, CDCl₃) δ +35.2 ppm.

c) Conversion of (12) into8-Diphenylphosphinoyl-2-naphthalen-1-yl-1,2,3,4-tetrahydroquinoline (13)

Following the procedure previously described for the synthesis ofcompound 6, 8-diphenylphosphinoyl-2-naphthalen-1-yl-1,2-dihydroquinoline(12) (8.3 g, 18.2 mmol) was quantitatively transformed into compound 13(8.3 g). ¹H NMR (400.13 MHz, CDCl₃) δ 8.0-9.9 (m, 1H, C^(5′)—H), 7.9-7.8(m, 1H, C^(8′)—H), 7.8-7.6 (m, 5H, C^(3′)/C^(6′/7′)—H/Ph-H), 7.7-7.4 (m,8H, Ph-H), 7.23 (bs, 1H, N—H), 7.18 (t, 1H, J=7.6 Hz, C⁵—H), 7.12 (d,1H, J=7.2 Hz, C^(2′)—H), 7.06 (d, 1H, J=7.2 Hz, C^(4′)—H), 6.71 (ddd,1H, J=14.4, 8.0, 1.2 Hz, C⁷—H), 6.51 (td, 1H, J=7.2, 2.4 Hz, C⁶—H), 6.41(t, 1H, J=1.6 Hz, C²—H), 2.9-2.8 (m, 1H, C^(4a)—H), 2.7-2.6 (m, 1H,C^(4b)—H), 2.3-2.2 (m, 1H, C^(3a)—H), 2.0-1.9 (m, 1H, C^(3b)—H) ppm; ¹³CNMR (100.61 MHz, CDCl₃) δ 149.8, 149.7, 139.6, 133.7, 133.3, 132.9,132.8, 132.1 (d, J=10.1 Hz), 131.8 (d, J=8.0 Hz), 131.7 (d, J=7.1 Hz),131.5 (d, J=12.1 Hz), 130.0, 128.8, 128.3 (d, J=12.1 Hz), 127.2, 125.8,125.4, 125.2, 123.40, 122.4, 121.6 (d, J=8.1 Hz), 133.4, 133.3, 110.9,109.9, 51.5, 27.8, 25.9 ppm; ³¹P NMR (161.97 MHz, CDCl₃) δ +34.6 ppm;HPLC (DAICEL-CHIRAPAK-AD, Hexane:IPA 60:40, 1 mL/min, 25° C., 210 nm)τ₁=7.23, τ₂=14.6.

d) Conversion of (13) into8-Diphenylphosphino-2-naphthalen-1-yl-1,2,3,4-tetrahydroquinoline (14)

Following the procedure described for compound7,8-diphenylphosphinoyl-2-naphthalen-1-yl-1,2,3,4-tetrahydroquinoline(13) (8.3 g, 18.1 mmol) was reduced to give compound 14 (5.0 g) as awhite solid in 62% yield. ¹H NMR (400.13 MHz, CDCl₃) δ 7.89 (d, 1H,J=8.0 Hz, C^(5′)—H), 7.73 (d, 1H, J=7.6 Hz, C^(8′)—H), 7.61 (d, 1H,J=8.0 Hz, C^(2′)—H), 7.4-7.2 (m, 12H, C^(6′/7′)—H/Ph-H), 7.17 (t, 1H,J=7.6 Hz, C^(3′)—H), 7.12 (d, 1H, J=6.0 Hz, C^(4′)—H), 6.94 (d, 1H,J=7.2 Hz, C⁵—H), 6.61 (td, 1H, J=7.2, 1.6 Hz, C⁷—H), 6.50 (t, 1H, J=7.2Hz, C⁶—H), 5.21 (dd, 1H, J=6.8, 2.4 Hz, C²—H), 4.99 (d, 1H, J=7.2 Hz,N—H), 2.9-2.8 (m, 1H, C^(4a)—H), 2.62 (m, 1H, C^(3b)—H), 2.3-2.1 (m, 1H,C^(3a)—H), 2.0-1.9 (m, 1H, C^(3b)—H) ppm; ¹³C NMR (100.61 MHz, CDCl₃) δ147.4, 147.2, 139.7, 135.5 (d, J=12.1 Hz), 135.4 (d, J=11.1 Hz), 133.9,133.8, 133.6 (d, J=13.1 Hz), 132.2, 130.2 (d, J=15.1 Hz), 128.8 (d,J=11.1 Hz), 128.6, 128.5, 128.4, 127.4, 125.9, 125.4 (d, J=13.1 Hz),123.3, 122.5, 120.3, 117.6, 116.4, 52.2, 28.7, 26.3 ppm; ³¹P NMR (161.97MHz, CDCl₃) δ −21.3 ppm.

EXAMPLE 4 Preparation of(R_(a),S_(c))-3,4-dihydro-(1-naphthyl)-QUINAPHOS 17

a) Synthesis of (R)- and (S)-2,2′ binaphthyl-1,1′-oxychlorophosphite

A suspension of (R)- or (S)-2,2′-binaphthyl (8.6 g, 30 mmol) and1-methyl-2-pyrrolidone (0.001 g, 0.01 mmol) in PCl₃ (26 mL, 300 mmol)was warmed to 75° C. and then stirred for 5 mins. Excess PCl₃ wasremoved under reduced pressure and then final traces removed byazeotropic distillation with toluene (3×10 mL) in vacuo. Productsobtained as white solids and were taken forward as solutions in toluene.

b) Conversion of (14)) to(R_(a),S_(c))-3,4-dihydro-(1-naphthyl)-QUINAPHOS 17

To a solution of8-diphenylphosphino-2-(1-naphthyl)-1,2,3,4-tetrahydro-quinoline 14(1.858 mmol, 824 mg) in dry THF (20 mL) under Ar, phenyllithium (1 eq,c=1.84 mol/L in di-n-butylether/Cyclohexane, 1.01 mL) was added at −20°C. and the resulting solution was stirred for 1 h at the sametemperature. (R)-1,1′-binaphthyl-2,2′-dioxychlorophosphite (1 eq, c=0.5mol/L in toluene, 3.72 mL) was then added and the resulting mixture wasslowly allowed to warm to RT and stirred for an additional hour. Afterremoval of the volatiles under vacuum, the residue was re-crystallisedfrom dry toluene (18 mL) adding dry ethanol (24 mL). After removal ofthe mother liquor the title compound was obtained as a white solid(696.7 mg) with a diastereomeric purity of 95:5 R_(a),S_(c):R_(a),R_(c).A second re-crystallisation from toluene (19 mL) ethanol (15 mL) yieldeddiastereomerically pure (R_(a),S_(c))-17 (368.8 mg, 26%). ¹H NMR (600.07MHz, CDCl₃, 296 K) δ 8.25 (d, J=8.7 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H),7.83 (d, J=8.7 Hz, 2H), 7.79 (d, J=8.7 Hz, 1H), 7.60-7.52 (m, 4H),7.49-7.35 (m, 9H), 7.35-7.25 (m, 9H), 7.16-7.10 (m, 1H), 7.06-6.98 (m,2H), 6.16 (d, J=8.6 Hz, 1H), 6.11 (t, J=7.6 Hz, 1H), 5.65 (t, J=8.3 Hz,1H), 3.20-3.09 (m, 1H), 2.82-2.73 (m, 1H), 2.68-2.59 (m, 1H), 1.66-1.55(m, 1H) ppm. ³¹P NMR (242.91 MHz, CDCl₃, 296 K) δ 138.2 (d, J=184.9 Hz,P(O)₂N), −19.9 (d, J=184.9 Hz, PPh₂) ppm.

EXAMPLE 5 Synthesis of [Rh(cod)(PP*)][BF₄],PP*≡(R_(a),S_(c))-3,4-Dihydro-(1-Nph)-QUINAPHOS 18

To a stirred solution of(2,4-acetylacetonato)-1,5-cyclooctadien-rhodium(I) (149.2 μmol, 46.3 mg)in dry THF (6 mL) under Ar, HBF₄.Et₂O (179 μmol, 25 μL, 1.2 eq) wasadded. After stirring for 10 min, a solution of (R_(a),S_(c))-17 (149.2μmol) in THF (7 mL) was added dropwise. The mixture was stirred for 30min and the solution was concentrated under vacuum (ca. 5 mL). By addingdry pentane (15 mL) a yellow solid precipitated which was collected anddried under vacuum (148.8 mg). This solid was re-crystallised fromCH₂Cl₂ (5 mL)/diethylether (25 mL) in order to remove occluded THFmolecules. The title compound was obtained as a yellow solid (94.3 mg,60%). ³¹P NMR (121.28 MHz, CDCl₃, 300 K) δ 137.8 (dd, J=251.0 Hz, J=68.2Hz, P(O)₂N), 23.5 (dd, J=136.6 Hz, J=68.2 Hz, PPh₂) ppm.

EXAMPLE 6 Asymmetric Hydrogenation with 18

In a Ar-flushed stainless steel autoclave 1 mL of a stock solution ofthe substrate (1 M, 1 mmol) and 1 mL of a stock solution of[Rh(cod)(18)][BF₄] (1 mM, 1 μmol) in CH₂Cl₂ were introduced. Theautoclave was pressurised with H₂ (30 bar) and the stirrer was switchedon. After the reaction time given in the table, the autoclave was ventedand the reaction mixture analyzed by GC. The results were as follows;

Substrate

Product

conv. [%]   >99   >99 t [min]     5     3 Sub/Rh    1000    1000 ee [%]  >99 (S)   >99 (R) TOF [h⁻¹] >12000 >15000

1. A chiral phosphorus compound of formula (I):

wherein R¹, R², R³, R⁴, R⁵ are chiral or achiral groups selected fromthe list consisting of substituted or unsubstituted straight-chain,branched-chain or cyclic aliphatic or aromatic groups and which, in thecase of the pairs R¹/R² and R⁴/R⁵, may be interconnected to form a ring.2. A compound according to claim 1 wherein R¹, R², R³, R⁴ or R⁵ areindependently selected from the group consisting of methyl, ethyl,n-propyl, i-propyl, n-butyl, t-butyl, hexyl, F(CF₂)_(m)(CH₂)_(n) wherem=1-10 and, n=0-4, cyclohexyl, menthyl, allyl, benzyl, —CH₂O(CH₂)₂OCH₃,phenyl, tolyl, anisyl, trifluoromethylphenyl, F(CF₂)_(m)(CH₂)_(n)C₆H₄—where m=1-10 and n=0-4, bis(tri-fluoromethyl)phenyl, chlorophenyl,pentafluorophenyl, hydroxyphenyl, carboxyphenyl, NaO₃SC₆H₄—, naphthyl,fluorenyl, pyridyl or furyl.
 3. A compound according to claim 1, whereinR¹ and R² are interconnected to form substituted or unsubstituted chiralor achiral bridges which are derived from the skeletons —(CH₂)_(n) wheren=2-4, —CH(CH₃)CH(CH₃)—, —CH(CH₃)CH₂CH(CH₃)—, 1,1′-bipheny-2,2′-diyl or1,1′-binaphth-2,2′-diyl.
 4. A compound according to claim 1, wherein R⁴and R⁵ are introduced using the alcohols methanol, ethanol, isopropanol,benzyl alcohol, cyclohexanol, allyl alcohol, phenol, methylphenol,chlorophenol, naphthol, furfural, ethylene glycol, 1,3-propanediol,1,3-pentanediol, cyclohexanediol, glycerol, monosaccharides,oligosaccharides, catechol, 2,2′-dihydroxy-1,1′-biphenyl,3,3′,5,5′-tetra-tert-butyl-2,2′-di-hydroxy-1,1′-biphenyl,3,3′-di-tert-butyl-2,2′-dihydroxy-5,5′-dimethoxy-1,1′-biphenyl,5,5′-dichloro-4,4′,6,6′-tetramethyl-2,2′-dihydroxy-1,1′-biphenyl or2,2′-dihydroxy-1,1′-binaphthyl.
 5. A method for preparing a compoundaccording to claim 1, comprising a step of selectively hydrogenating acompound of formula (VI) to hydrogenate the carbon-carbon double bond inthe 1,2-dihydroquinoline ring.


6. A method according to claim 5 wherein the compound of formula (VI) isformed by steps comprising; (i) alkylating a compound of formula (II)with a nucleophilic reagent R³M to form compounds of formula (III), and(ii) either (a) hydrolysing the compounds of formula (III) to formcompounds of formula (IV) then reacting compounds of formula (IV) with(R⁵O)(R⁴O)PCl, or (b) reacting the compounds of formula (III) with PCl₃to form compounds of formula (V) and then reacting compounds of formula(V) with a base and alcohols R⁴OH and R⁵OH.


7. A method according to claim 5 wherein the selective hydrogenation isperformed using a heterogeneous palladium catalyst.
 8. A method forpreparing a compound according to claim 1, comprising a step of reactinga compound of formula (X) with (R⁵O)(R⁴O)PCl.


9. A method according to claim 8 wherein the compound (X) is prepared byselectively hydrogenating a compound of formula (IV) to hydrogenate thecarbon-carbon double bond in the dihydroquinoline ring.


10. A method according to claim 9 wherein the compound of formula (IV)is prepared by steps comprising; (i) alkylating a compound of formula(II) with a nucleophilic reagent R³M to form compounds of formula (III),and (ii) hydrolysing the compounds of formula (III).


11. A method according to claim 10 wherein the compound of formula (IV)is prepared by steps comprising; (i) enantioselectively alkylating acompound of formula (II) with a nucleophilic chiral reagent R³M or witha nucleophilic reagent R³M in the presence of a chiral auxiliary orcatalyst and then (ii) treating the reaction product with aqueous acidto form enantioenriched compounds (IVa) or (IVb).


12. A method according to claim 9 wherein the compound of formula (IV)is prepared by steps comprising; (i) alkylating a compound of formula(VII) in which X is a group selected from bromide, chloride, iodide,hydroxy, alkoxy, tosylate, mesylate, nonaflate, fluoride or triflatewith a nucleophilic reagent R³M and then hydrolysing the reactionproduct to form a compound of formula (VIII) and (ii) reacting thecompound of formula (VIII) with a phosphorylating compound.


13. A method according to claim 12 wherein the compound of formula (IV)is prepared by steps comprising; (i) enantioselectively alkylating acompound of formula (VII) with a nucleophilic chiral reagent R³M or witha nucleophilic reagent R³M in the presence of a chiral auxiliary orcatalyst and then treating the reaction product with aqueous acid toform enantiomerically enriched compounds (VIIIa) or (VIIIb), and (ii)reacting the compound (VIIIa) or (VIIIb) with a phosphorylatingcompound.


14. A method according to claim 9 wherein the compound of formula (IV)is prepared by steps comprising; (i) performing a ring closingmetathesis of compounds of formula (XXVIIIb) or (XXVIIIa) to formcompounds (XXIXb) or (XXIXa), respectively, and (ii) cleaving the tosylgroups to form compounds (IVb) or (IVa).


15. A method according to claim 8 wherein the compound (X) is preparedby steps comprising; (i) selectively hydrogenating a compound of formula(VIII), in which X is a group selected from bromide, chloride, iodide,hydroxy, alkoxy, tosylate, mesylate, nonaflate, fluoride or triflate, tohydrogenate the carbon-carbon double bond in the dihydroquinoline ringto form a compound of formula (IX), and (ii) phosphorylating thecompound of formula (IX) with a phosphorylating compound.


16. A method according to claim 15 wherein the compound of formula(VIII) is prepared by steps comprising; reacting an aniline compound offormula (XIII) in which X is a group selected from bromide, chloride,iodide, hydroxy, alkoxy, tosylate, mesylate, nonaflate, fluoride ortriflate, with a carboxylic acid, ester or chloride of formulaR⁷OCHR³CH₂COOR⁶ in which R⁶ is H, Cl or C1-C10 alkyl and R⁷ is C1-C10alkyl, Tosyl, Mesyl, Triflate, Acetyl, H or a silyl protecting group, togive compounds (XIV), (ii) cyclising the compounds (XIV) to give ketones(XV), (iii) reducing the ketones (XV) to give alcohol compounds (XVI),and (iv) dehydrating the alcohol compounds (XVI).


17. A method according to claim 15 wherein the compound of formula(VIII) is prepared by steps comprising; (i) performing a ring closingmetathesis of compounds of formula (XXVb) or (XXVa) to form compounds(XXVIb) or (XXVIa), respectively, and (ii) cleaving the tosyl groups toform compounds (VIIIb) or (VIIIa).


18. A method according to claim 8 wherein the compound (X) is preparedin enantiomerically enriched form (Xa) or (Xb) by asymmetricallyhydrogenating a compound of formula (XII) in the presence of ahomogeneous transition metal hydrogenation catalyst having one or morechiral ligands.


19. A method according to claim 8 wherein the compound (X) is preparedin enantiomerically enriched form (Xa) or (Xb) by steps comprising; (i)asymmetrically hydrogenating a compound of formula (XI), in which X is agroup selected from bromide, chloride, iodide, hydroxy, alkoxy,tosylate, mesylate, nonaflate, fluoride or triflate, in the presence ofa homogeneous transition metal hydrogenation catalyst having one or morechiral ligand to produce enantiomerically enriched intermediates (IXa)or (IXb), and (ii) reacting compound (IXa) or (IXb) with aphosphorylating compound.


20. A method according to claim 8 wherein the compound (X) is preparedin enantiomerically enriched form (Xa) or (Xb) by steps comprisinghydrogenating a ketone compound of formula (XXII).


21. A method according to claim 20 wherein the ketone compound offormula (XXII) is prepared by steps comprising; (i) reacting a phosphineof formula (XX) in which Y is selected from fluoride, chloride, bromide,iodide, tosyl, mesyl, triflate, or nonaflate, with a chiral amine offormula H₂NCH(CH₃)Ar, in which Ar is an aryl group, to form chiralcompound of formula (XXI), and (ii) reacting the chiral compound (XXI)with an unsaturated carboxylic acid, ester or chloride of formulaR³CH═CHCOOR⁶ in which R⁶ is H, Cl or C1-10 alkyl.


22. A method according to claim 20 wherein the ketone compound offormula (XXII) is prepared by steps comprising; (i) reacting asubstituted phenyl compound of formula (XVII) in which X and Y areselected from fluoride, chloride, bromide, iodide, tosyl, mesyl,triflate, or nonaflate, with a chiral amine of formula H₂NCH(CH₃)Ar, inwhich Ar is an aryl group, to form chiral compound (XVIII), (ii)reacting the chiral compound (XVIII) with an unsaturated carboxylicacid, ester or chloride of formula R³CH═CHCOOR⁶ in which R⁶ is H, Cl orC1-10 alkyl, to form a ketone of formula (XIX), and (iii) reacting theketone (XIX) with a phosphorylating compound.


23. A chiral phosphorus compound of formula (X):

wherein R¹, R², R³ are chiral or achiral groups selected from the listconsisting of substituted or unsubstituted straight-chain,branched-chain or cyclic aliphatic or aromatic groups and in which thepair R¹/R² may be interconnected to form a ring.
 24. A catalystcomprising a phosphorus compound according to claim
 1. 25. A process forpreparing one or more optically active products, said process comprisingpreparing said optically active products in the presence of a catalystaccording to claim
 24. 26. A process according to claim 25, wherein saidcatalyst consists of said phosphorus compound and a transition metal ora transition metal compound.
 27. A process according to claim 25,wherein said preparing comprises enantioselective hydroformylation. 28.A process according to claim 25, wherein said preparing comprisesenantioselective hydrogenation.
 29. A process according to claim 25,wherein said preparing comprises enantioselective hydroboration.